Ibuprofen (p-isobutylhydratropic acid) is a non-steroidal composition that has long been recognized as being useful in the treatment of pain, inflammation, and fever. More particularly, ibuprofen has been found in clinical studies to be very effective in the treatment of the signs and symptoms of rheumatoid arthritis and osteoarthritis, the relief of mild to moderate pain, and the treatment of primary dysmenorrhea, among other things. Ibuprofen is at least as effective as other available high potency compounds, such as indomethacin and phenylbutazone, but without their attendant side effects, such as increased toxicity. Also, ibuprofen is obtainable over the counter in certain dosages, whereas other high potency compounds are not.
There has been a long felt need for an analgesic composition which is safe, effective, and capable of being formed into a pharmaceutically elegant product. Two compositions tried in the past are aspirin and acetaminophen. There are several disadvantages in using these compositions as compared with using ibuprofen. First, the analgesia produced by a given amount of aspirin or acetaminophen is less than that produced by the same amount of ibuprofen. Second, acetaminophen compositions lack anti-inflammatory activity. Third, aspirin compositions produce significantly more gastrointestinal distress in some patients. Fourth, aspirin has been reported linked to Reye's syndrome in children. Fifth, acetaminophen has been reported to cause liver failure in some patients and has been more recently been questioned about its possible link to renal disorders.
Although ibuprofen is a significantly better analgesic than aspirin or acetaminophen, there are notable problems in preparing satisfactory dosage forms of ibuprofen. These problems include the facts that ibuprofen is insoluble in water, has a very bitter taste, and is unstable in aqueous media.
Applicant has essentially solved all of these problems in one stroke by preparing and using alkali metal salts of ibuprofen. These salts are easily dissolved in water, they permit preparation of pharmaceutical compositions which are virtually lacking in the unpleasant taste sensations of ibuprofen, and they are stable in aqueous media. They are more easily taken up by the body and they involve less gastrointestinal distress than conventional ibuprofen compositions.
There has been some theoretical speculation about the possibility of preparing alkali metal salts of ibuprofen, but to Applicant's knowledge, there has never been anything indicating that such salt have ever been put in the hands of the public. To Applicant's knowledge, there has never been an alkali metal salt of ibuprofen actually prepared by any process, nor has there been any publication of any information sufficient to enable a person skilled in the art to make and use an alkali metal salt of ibuprofen or appreciate its advantageous properties.
For example, Gardano et al. U.S. Pat. No. 4,536,595 describes the preparation of an alpha-aryl-propionic acid from a corresponding organic halide and carbon monoxide in the presence of a catalytic system based on cobalt carbonyl complexes and alkaline metal hydroxides. The patent refers to preparation of alkaline salts of alpha-aryl-propionic acids, but does not describe the preparation of those salts beyond the description of a process involving a liquid composition which might contain the ions that if bonded together theoretically would be an alkali metal salt of an alpha-aryl-propionic acid. The patent does not describe a process which produces an actual salt, even though it says it does. In all instances, the only thing produced by the processes of the patent is the alpha-aryl-propionic acid and not a salt. There thus is no enabling disclosure of such a salt.
Canadian Patent No. 1 197 254 describes a process which is similar to that of the Gardano et al. patent described above. Likewise, there is no description of how alkaline salts of alpha-aryl-propionic acids are to patent be made and thus this patent is like the Gardano et al. patent in failing to enable one skilled in the art to achieve such alkaline salts.
U.S. Pat. No. 3,385,886 describes phenyl propionic acids. It says that the salts of the acids can be made by reacting the acids with organic or inorganic bases. There is no enabling disclosure of how to prepare alkali metal salts of ibuprofen.
Another patent which can only be said to identify an alkali metal salt of ibuprofen as a theoretical possibility and not to describe it in an enabling manner is Schmidt U.S. Pat. No. 4,404,210, which mentions aluminum, calcium, potassium, and sodium salts of ibuprofen.
This application is the first enabling disclosure of alkali metal salts of ibuprofen and a process of making them It is also the first instance of identifying the advantageous properties of such salts of ibuprofen and its uses in alleviating pain, inflammation, and fever. It likewise is the first instance of teaching how the salts may be put into pharmaceutically acceptable and elegant dosage forms.